Suppression of uracil-DNA glycosylase induces neuronal apoptosis

被引:48
作者
Kruman, II
Schwartz, E
Kruman, Y
Cutler, RG
Zhu, XX
Greig, NH
Mattson, MP
机构
[1] Sun Hlth Res Inst, Sun City, AZ 85351 USA
[2] NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA
[3] NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA
[4] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
关键词
D O I
10.1074/jbc.M408025200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A chronic imbalance in DNA precursors, caused by one-carbon metabolism impairment, can result in a deficiency of DNA repair and increased DNA damage. Although indirect evidence suggests that DNA damage plays a role in neuronal apoptosis and in the pathogenesis of neurodegenerative disorders, the underlying mechanisms are poorly understood. In particular, very little is known about the role of base excision repair of misincorporated uracil in neuronal survival. To test the hypothesis that repair of DNA damage associated with uracil misincorporation is critical for neuronal survival, we employed an antisense (AS) oligonucleotide directed against uracil-DNA glycosylase encoded by the UNG gene to deplete UNG in cultured rat hippocampal neurons. AS, but not a scrambled control oligonucleotide, induced apoptosis, which was associated with DNA damage analyzed by comet assay and up-regulation of p53. UNG mRNA and protein levels were decreased within 30 min and were undetectable within 6-9 h of exposure to the UNG AS oligonucleotide. Whereas UNG expression is significantly higher in proliferating as compared with nonproliferating cells, such as neurons, the levels of UNG mRNA were increased in brains of cystathionine beta-synthase knockout mice, a model for hyperhomocysteinemia, suggesting that one-carbon metabolism impairment and uracil misincorporation can induce the up-regulation of UNG expression.
引用
收藏
页码:43952 / 43960
页数:9
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